Prostaglandin F{HD 3{301 {0 {B analogs

ABSTRACT

This disclosure relates to prostaglandins of the PG3 series including PGE3, PGF3 , PGF3 , PGA3, and PGB3, to various analogs of those in racemic form, and to novel processes for making those. This disclosure also relates to certain fluorine and alkyl substituted analogs and certain acetylenic analogs of PGE3, PGF3 , PGF3, PGA3, and PGB3 in both racemic and optically active form, and to processes for making those. These various analogs are useful for the same pharmacological purposes as the known optically active forms of PGE3, PGF3 , PGF3 , PGA3, and PGB3, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement, fertility control, and wound healing.

United States Patent Axen 1 Apr. 22, 1975 l l PROSTAGLANDIN F ANALOGS[56] References Cited {75] Inventor: Udo F. Axen, Comstock Township,FORElGN PATENTS OR APPLICATIONS Kalamazoo Counlik Mich- 2,118,68611/1971 Germany; 260/468 [73] Assignee: The Upjohn Company, Kalamazoo.

Mi h Primary Eraminer-Robert Gerstl 1 [-2] F1led. Nov. 5. 1973 [57]ABSTR CT [21] Appl' 412972 This disclosure relates to prostaglandins ofthe P6 se- Related US. Application Data ries including PGE3. PGFZM. PGFPGA and [63] Continuation-impart of Scr. No. H1032. Feb. 2. 3 to Variousanalogs of those in racemic forml9 l. Pat. No. 3.775.462. which is a andto novel processes for making those. This disclocontinuation-in-part ofScr. No. 30312. April 20. sure also relates to certain fluorine andalkyl substi- 1970. flbflflduflcdtuted analogs and certain acetylenicanalogs of PGE;,, 1 PGFihn POE- PGAn. and P68 in both racemic l l Cl260/468 D: 260/247; 260/2 7.2 and optically active form. and toprocesses for making 260/268 R; 260/243.65; 260/326.3; 260/ those. Thesevarious analogs are useful for the same 26 6; 260/4104 R; 260/413;pharmacological purposes as the known optically ac- 260/ 0/ R. 6 tiveforms of PGE3. PGFZhh PGF PGA and 260/5011; 2 0/50L-l5: 260/50] l PGBincluding anti-ulcer. inhibition of platelet aggre- 26 5 1 60514 Dgation, increase of nasal patency, labor inducement. [5 l 1 int. Cl C07C61/32; C07C 6l/74 fertility c nU I and wound healing, [58] FieldofSearch 260/468 D. 514 D 23 Claims, No Drawings PROSTAGLANDIN F ANALOGSCROSS REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of copending application Ser. No. 112,032, filedFeb. 2, 1971, now US. Pat. No. 3,775,462 which is a continuationin-partof copending application Ser. No. 30,312. filed Apr. 20, 1970, and nowabandoned.

BRIEF DESCRIPTION OF THE INVENTION This invention relates tocompositions of matter. and to methods and intermediates for producingthem. In particular, the several aspects of this invention relate toracemic prostaglandin E (PGE racemic prostaglandin F (PGF and PGF Bracemic prostaglandin A (PGA prostaglandin B (P68 to the correspondingacetylenic prostaglandins, 5,6,17,18- dehydro-PGE 5,6,17,18-dehydro-PGF5.6,l7,l8- dehydro-PGF B 5,6,17.l8-dehydro-PGB to analogs of thoseprostaglandins and 5,6,17,18-dehydro-prostaglandins; to processes forproducing racemic PGE PGF PGF B PGA PO8 the corresponding5,6,17,18-dehydroprostaglandins, and the analogs thereof; to processesfor revolving the racemates into the dand lforms; and to chemicalintermediates useful in those methods.

Optically active PGE (the natural or dconfiguration) is a knownsubstance. Bergstrom, Science 157, 382 (1967); Samuelson. J. Amer. Chem.Soc., 85, 1878 (1963). Optically active PGF (a and B). obtained by theborohydride reduction of optically active PGE is also a known substance;Samuelson, Biochemica Biophysica Acta, 84, 707 (1964); so also isoptically active PGA British Specification No. 1,097,533. Opticallyactive PGE optically active lHz, and optically active PGF are alsodisclosed in British specification No. 1,040,544.

The prior art methods for producing prostaglandins are costly anddifficult, the necessary biological materials are limited, and themethods are not adaptable to production of a wide variety ofprostaglandin intermediates and analogs.

It is the purpose of this invention to provide processes for theproduction of compounds with prostaglandimlike activity in substantialamounts and at reasonable cost. The useful compounds produced accordingto the processes of this invention comprise racemic POE racemic PGFracemic PGF p racemic PGA racemic PGB the corresponding 5,6,17,18-dehydro-prostaglandins, and other hitherto unavailable racemic andoptically active analogs thereof such as the enantiomorphs (dand lforms)of PGB and the 5,6,17,18-dehydro compounds.

PGE has the following structure:

PGF has the following structure:

5,6,l7,l8-dehydro-PGA and The above formulas represent the naturalconfiguration. Racemic PGE PGF GFgp, PGA and PGB are each represented bythe combination of one of the above formulas and the mirror image(enantiomorph) of that formula. See Nature, 212, 38 (1966) fordiscussion of the stereochemistry of the prostaglandins.

In formulas I, II, III, IV, and V, as well as in the formulas givenhereinafter, broken line attachments to the cyclopentane ring indicatesubstituents in alpha configuration, i.c., below the plane of thecyclopentane ring. Heavy solid line attachments to the cyclopentane ringindicate substituents in beta configuration, i.c., above the plane of.the cyclopentane ring. I

sr FM, GFap, PGA and PGB are derivatives of prostanoic acid which hasthe following structure and atom numbering:

A systematic name for prostanoic acid is 7-[(2B- octyl )cyclopentl a-yl]heptanoic acid.

Compounds similar to formula VI but with carboxylterminated side chainsattached to the cyclopentane ring in beta configuration are designatedS-isoprostanoic acids, and have the following formula:

COOH

A systematic name for iso-prostanoic acid is 7-[(2B- octyl)-cyclopent-lB-yllhcptanoic acid.

Prostaglandin E and its analogs and isomers produced according to theprocesses of this invention are represented by the formula:

wherein R, is hydrogen. alkyl of one to 8 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, phenyl substituted with one to 3 chloro oralkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in theB-position with 3 chloro, 2 or 3 bromo, or l, 2, or 3 iodo; wherein R isalkyl of one to 4 carbon atoms, inclusive substituted with zero to 3fluoro; wherein R and R are hydrogen or alkyl of one to 4 carbon atoms,-inclusive; wherein n is an integer of one to 4, inclusive; wherein A isalkylene of one to 10 carbon atoms, inclusive, substituted with zero to2 fluoro, and with one to 5 carbon atoms, inclusive, between COOR, and

and pharmacologically acceptable salts thereof wherein R, is hydrogen.

Prostaglandin F and its analogs and isomers produced according to theprocesses of this invention are represented by the formula:

wherein R R R R and A are as defined above for formula Vllle, andpharmacologically acceptable salts thereof when R, is hydrogen.

Prostaglandin A and its analogs and isomers produced accordingto theprocesses of this invention are represented by-the formula:

wherein R,, R R R and A are as defined above for formula VIIIe, and thepharmacologically acceptable salts thereof wherein R is hydrogen.

Prostaglandin B and its analogs and isomers (including itsenantiomorphs) produced according to the processes of this invention arerepresented by the formula:

wherein R,, R R R and A are defined above for formula VIIIe, andpharmacologically acceptable salts thereof wherein R is hydrogen.

The wavy Iine,-, as used above, and elsewhere herein, includes bothconfigurations, i.e., alpha and beta, or endo or exo. The word racemicindicates an equal mixture of a compound of the formula shown, which isthe natural configuration, and its enantiomorph.

Compounds of formula Ville, lxe, Xe, and Xle have their counterpartwhere the cis-ethylenes are dehydro, i.e., ethynylene. These dehydroanalogs here designated as VIIId, IXd, Xd, and Xld, are intermediates,as will be shown, for making the compounds of formulas VIIIe, IXe, Xe,and XTe. Racemic dehydro compounds give raeemic final products. Anenantiomorph of the dehydro compound (the configuration as shown or themirror image thereof) gives the corresponding enantiomorph of the finalcompound.

Also included in formulas VIII, IX, X, and XI are separate isomerswherein the side chain hydroxy is in R or S configuration. All of thecompounds encompassed by formulas VIII, IX, and X have the trans Cl-I=C-R CR OH side chain attached in beta configuration.

Formulas VlIIe, IXe, Xe, and Xle represent PGE PGF PGA and PGBrespectively, when in these formulas R R and R, are each hydrogen, n is1, R is ethyl, A is trimethylene, the attachment of CI-I-CI-I=CI-IA--COOR, to the cyclopentane ring is inalpha configuration, andthe configuration of the side chain hydroxy is S.

With regard to formulas VIII to XI, inclusive, examples of alkyl of oneto 4 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, andisomeric forms thereof. Examples of alkyl of one to 8 carbon atoms,inclusive, are those given above, and pentyl, hexyl, heptyl, oetyl, andisomeric forms thereof. Examples of alkyl of one to 10 carbon atoms,inclusive, are those given above, and nonyl, decyl, and isomeric formsthereof. Examples of eycloalkyl of 3 to 10 carbon atoms, inclusive,which includes alkyl-substituted cycloalkyl, are eyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyelobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tertbutylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to l2 carbon atoms, inclusive, are benzyl, phenethyl, l-phenethyl,l-phenylethyl, 2-phenylpropyl. 4-phenylbutyl, 3- phcnylbutyl, 2-(l-naphthylethyl and l-( 2- naphthylmethyl). Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p-chlorophenyl, m-chlorophenyl, ochlorophenyl,2,4-dichlorophenyl. 2,4,6- trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro- S-methylphenyl.

Examples of alkylene of one to carbon atoms, inclusive, are methylene.ethylene, trimethylene, tetramethylene, pentamethylene, and isomericbranched chain forms thereof, 1-, 2', and 3- methylpentamcthylene, l-,2-, 3-ethylpentamethylene. 1-, 2-, and 3-propylpentamethylene, l-, 2-,and 3- butylpentamethylene, and l-, 2-, and 3-pentylpentamethylene.

Examples of alkyl of one to 4 carbon atoms inclusive, substituted withone to 3 fluoro, are 2-fluoroethyl,

2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, 3,4- difluorobutyl,2,2,2-trifluorocthyl, and 4,4,4- trifluorobutyl.

Examples of alkylene of one to 10 carbon atoms, inelusive, substitutedwith one or 2 fluoro, have the formulas CH CHF, -CH CF -CH CH CHFC H CHCH CH CF PGE PGF PGF p PGA and PGB and their esters andpharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bcrgstrom et al.,Pharmacol. Rev. 20, l 1968), and references cited therein. A few ofthose biological responses are systemic arterial blood pressure loweringin the case of PGE PGF fi and PGA as measured, for example, inanesthetized (pentobarbital sodium) pentoliniumtreated rats withindwelling aortic and right heart cannulas; pressor activity, similarlymeasured, for PGF stimulation of smooth muscle as shown, for example, bytests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon;potentiation of other smooth muscle stimulants; antilipolytic activityas shown by antagonism of epinephrine-induced mobilization of free fattyacids or inhibition of the spontaneous release of glycerol from isolatedrat fat pads; inhibition of gastric secretion in the case of PGE and PGAas shown in dogs with secretion stimulated by food or histamineinfusion; activity on the central nervous system; decrease of bloodplatelet adhesiveness as shown by platelet-toglass adhesiveness, andinhibition of blood platelet aggregation and thrombus formation inducedby various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of PGE and PBG stimulation of epidermal proliferationand keratinization as shown when applied in culture to embryonic chickand rat skin segments.

Optically active PGEg, and its esters and pharmacologically acceptablesalts, are also extremely potent in causing the same biologicalresponses as PGE- Horton et al., Brit. J. of Pharm. and Chemotherapy,21, I82 1963 Bergstrom et al.. acta physiol. science, 59. 493 (1963);Heinberg et al., .1. Clinic. Investigation. 43, 1533 (I964); Bergstromet al.. acta physiol. science, 60, 170 (I964); and Sandberg et al.. ActaObstctrica et Gynecolojica Science, 43, (1964). Optically active PGF andPGA which are obtained from optically active PGE also cause the samebiological responses as PGF and PGA Because of these biologicalresponses, these known prostaglandins are useful to study, prevent,control. or alleviate a wide variety of diseases and undesirablephysiological conditions in birds and mammals, including humans, usefuldomestic animals, pets. and zoological specimens, and in laboratoryanimals, for example, mice, rats, rabbits, and monkeys.

For example, these compounds, and especially PGE are useful in mammals,including man, as nasal decongestants. For this purpose, the compoundsare used in a dose range of about 10 ug. to about 10 mg. per ml. of apharmacologically suitable liquid vehicle or as an aerosol spray, bothfor topical application. PGE is similarly useful when administered inequivalent doses.

POE- and PGA are useful in mammals, including man and certain usefulanimals, e.g., dogs and pigs, to reduce and control excessive gastricsecretion, thereby reducing or avoiding gastrointestinal ulcerformation, and accelerating the healing of such ulcers already presentin the gastrointestinal tract. For this purpose, the compounds areinjected or infused intravenously, subcutaneously, or intramuscularly inan infusion dose range about 0.1 ug. to about 500 pg. per kg. of bodyweight per minute, or in a total daily dose by injection of infusion inthe range about 0.1 to about 20 mg. per kg. of body weight per day, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration. PCS-E and PGAare similarly useful when administered in equivalent doses.

PGE PGA PGF and PGF B are useful whenever it is desired to inhibitplatelet aggregation, to reduce the adhesive character of platelets, andto remove or prevent the formation of thrombi in mammals, including man,rabbits, and rats. For example, these compounds are useful in thetreatment and prevention of myocardial infarcts, to treat andpreventpost-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and otherclinical conditions in which the underlying etiology is associated withlipid imbalance or hyperlipidemia. For these purposes, these compoundsare administered systemically, e.g., intravenously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred. Doses in the rangeabout 0.004 to about 20 mg. per kg. of body weight per day are used, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration. PGE PGA PGFand PGF B are similarly useful when administered in equivalent doses.

PGE PGA PGF- and PGF- are especially useful as additives to blood. bloodproducts, blood substitutes, and other fluids which are used inartificial extracorporeal circulation and perfusion ofisolated bodyportions, e.g., limbs and organs, whether attached to the original body,detached and being preserved or prepared for transplant, or attached toa new body. During these circulations and perfusions, aggregatedplatelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal. to the perfused body portion, attached or detached. tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants. PGE PGA PFG 3aand PGF B are similarly useful when administered in equivalent doses.

PGE is extremely potent in causing stimulation of smooth muscle. and isalso highly active in potentiating other known smooth musclestimulators, for example, oxytocic agents, e.g., oxytocin, and thevarious ergot alkaloids including derivatives and analogs thereof.Therefore PGE is useful in place of or in combination with less thanusual amounts of these known smooth muscle stimulators, for example, torelieve the symptoms of paralytic ileus, to control or prevent atonicuterine bleeding after abortion or delivery, to aid in expulsion of theplacenta, and during the puerperium. For these purposes, PGE isadministered by intravenous infusion immediately after abortion ordelivery at a dose in the range about 0.01 to about 50 pg. per kg. ofbody weight per minute until the desired effect is obtained Subsequentdoses are given by intravenous, subcutaneous, or intramuscular injectionor infusion during puerperium in the range 0.01 to 2 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal. F'GE; is similarly useful whenadministered in equivalent doses.

POE- PGA and PGF B are useful as hypotensive agents to reduce bloodpressure in mammals, including man. For this purpose, the compounds areadministered by intravenous infusion at the rate about 0.01 to about 50pg. per kg. of body weight per minute or in single or multiple does ofabout 25 to 500 pg. per kg. of body weight total per day. PGE PGA andPGF p are similarly useful when administered in equivalent doses.

PGE PGF and PGF B are useful in place of oxytocin to induce labor inpregnant animals, including man, cows, sheep, and pigs, at or near term,or in pregnant animals with intrauterine death of the fetus from aboutweeks to term. For this purpose, the compound is infused intravenouslyat a dose 0.01 to 50 pg. per kg. of body weight per minute until or nearthe termination of the second stage of labor, i.e., expulsion of thefetus. These compounds are especially useful when the female is one ormore weeks post-mature and natural labor has not started, or 12 to 60hours after the membranes have ruptured and natural labor has not yetstarted. PGE PGF and PGF B are similarly useful when administered inequivalent doses.

PGF PGF B and PGE are useful for controlling the reproductive cycle inovulating female mammals, including humans and animals such as monkeys,rats, rabbits. dogs, cattle, and the like. For that purpose, PGF isadministered systemically at a dose level in the range 0.01 mg. to about20 mg. per kg. of body weight of the female mammal, advantageouslyduring a span of time starting approximately at the time of ovulationand ending approximately at the time of menses or just prior to menses.PGE PGF and PGF B are similarly useful when administered in equivalentcloses.

As mentioned above, PGE is a potent antagonist of epinephrine-inducedmobilization of free fatty acids. For this reason, this compound isuseful in experimental medicine for both in vitro and in vivo studies inmammals, including man, rabbits, and rats, intended to lead to theunderstanding, prevention, symptom alleviation, and cure of diseasesinvolving abnormal lipid mobilization and high free fatty acid levels,e.g., diabetes mellitus, vascular diseases, and hyperthyroidism. PGE issimilarly useful when administered in equivalent does.

PGE and PGB promote and accelerate the growth of epidermal cells andkeratin in animals, including humans, useful domestic animals, pets,zoological specimens, and laboratory animals. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These compounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts. PGEand P683 are similarly useful when administered in equivalent doses.

For these purposes, these compounds as well as the compounds of theinvention are preferably administered topically at or near the sitewhere cell growth and keratin formation is desired, advantageously anaerosol liquid or micronized powder spray, as an isotonic aqueoussolution in the case of wet dressings, or as a lotion, cream, orointment in combination with the usual pharmaceutieally acceptablediluents. In some instances, for example, when there is substantialfluid loss in the ease of extensive burns or skin loss due to othercauses, systemic administration is advantageous, for example, byintravenous injection or infusion, separate or in combination with theusual infusions of blood, plasma, or substitutes thereof. Alternativeroutes of administration are subcutaneous or intramuscular near thesite, oral, sublingual, buccal, rectal, or vaginal. The exact dosedepends on such factors as the route of administration, and the age,weight, and condition of the subject. Especially for topical use, theseprostaglandins are useful in combination with antibiotics, for example,gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, andoxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith eorticoid steroids, for example, hydrocortisone,prednisolone,methylprednisolone, and fluprednisolone, each of thesebeing used in the combination at the usual concentration suitable forits use alone.

Racemic PGE racemic PGF racemic PGF and racemic PGA each are useful forthe purposes described above for the optically active compounds. butthese racemic compounds offer the enormous advantage of being availablein unlimited quantities at much lower cost. Racemic PGB has likeadvantages and is useful for the same purposes as PGB Moreover. theseracemic compounds are easier to purify since they are produced bychemical reactions rather than by extraction from biological materialsor enzymatic reaction mixtures.

The PGE PGF PGA and P68 analogs and isomers cause correspondingbiological responses and are useful for corresponding purposes as PGEPGF PGA and P08 respectively.

To obtain the optimum combination of biological response specificity andpotency. certain compounds within the scope of formulas Vllle and lXeare preferred. As discussed above. those formulas represent the PGE-type compounds and the PGF type compounds. respectively. Referring toformulas Vllle and lXe, when -CH -CH=CHA-COOR is attached in alphaconfiguration and. in the case of formula IXe, when the ring hydroxy isalso attached in alpha configuration. the sterochemistry is typical ofthe known optically active P65, and PCP According to this invention,preferred formual Vllle and lXe compounds are those wherein CHCH=CHACOOR and ring hydroxy arc alpha. n is l and A is trimethylene. Ris hydrogen and R is hydrogen or methyl and R is ethyl. These preferredcompounds exhibit superior biological response specificity and/orpotency.

Certain compounds within the scope of formulas Vllle to Xle areespecially useful for one or more of the purposes stated above. becausethey have a substantially longer duration of activity than othercompounds within the generic formulas. including PGE PGF PGF PGA and P08and because they can be administered orally, sublingually,intravaginally. buccally. or rectally, rather than by the usualintravenous. intramuscular. or subcutaneous injection or infusion asindicated above for the uses of these known prostaglandins and the othercompounds encompassed by formulas Vllle to Xle. These qualities areadvantageous because they facilitate maintaining uniform levels of thesecompounds in the body with fewer. shorter. or smaller doses, and makepossible self-administration by the patient.

With reference to formulas Vllle to Xle, these special compounds includethose wherein A is -(CH ),,-Z. wherein h is zero, one. 2. or 3, and Z isethylene substituted by oneor 2 fluoro. methyl, or ethyl. or by onealkyl of 3 or 4 carbon atoms. These special compounds also include thosewherein R is ethyl, propyl, isopropyl. isobutyl, tert-butyl,3.3-difluorobutyl, 4,4-difluorobutyl, or 4,4.4-trifluorobutyl. Thesespecial compounds also include those wherein A is --(CH ),,-Z- as abovedefined, and R is ethyl, propyl, isopropyl. isobutyl. tert-butyl,3,3-difluorobutyl. 4.4- difluorobutyl, or 4,4.4-trifluorobutyl.Especially preferred among these special compounds are those wherein Rand R are both hydrogen.

In the case of Z, the divalent ethylene group, -CH- --CH is substitutedon either or both carbon atoms, i.e.. alpha and/or beta to thecarboxylate funcand similarly for ethyl. and for one fluoro and onemethyl. one fluoro and one ethyl. and one methyl and one ethyl. Z isalternatively ethylene substituted on either carbon atom with propyl,isopropyl. butyl. isobutyl. sec-butyl, or tert-butyl.

Although all of the special compounds just described have the specialadvantages of long duration and oral. sublingual intravaginal, andrectal routes ofadministration. there is a still more limited group ofcompounds encompassed by these formulas which have these qualities in aparticularly high degree. Those are the compounds wherein A is -CH -Z.i.c.. wherein b in -(CH2)b-Z is one, especially whenZ is ethylene withone fluoro or methyl, with 2 fluoro or 2 methyl on the same carbonatoms. or with butyl, isobutyl. sec-butyl. or tert-butyl on the carbonatoms alpha (adjacent) to the carboxylate function. the compoundswherein R is -C(CH CH CH(CH -CH CF;,, -CH CHF or CH CF CH and thecompounds wherein both A and R are both defined in these more limitedways.

Racemic PGEg, racemic PGF racemic PGF racemic PGA racemic P68 and theother compounds encompassed by formulas Vllle and Xle. are used for thepurposes described above in the free acid form. in ester form, or inpharmacologically acceptable salt form. When the ester form is used. theester is any of those within the above definition of R However. it ispreferred that the ester be alkyl of one to four carbon atoms.inclusive. Of those alkyl, methyl and ethyl are especially preferred foroptimum absorption of the compound by the body or experimental animalsystem.

Pharmacologically acceptable salts of these formula Vllle. IXe. Xe, Xlecompounds useful for the purposes described above are those withpharmacologically acceptable metal cations, ammonium, amine cations. or

quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals. e.g.. lithium. sodium, and potassium. and from the alkalineearth metals, e.g.. magnesium and calcium. although cationic forms ofother metals. e.g.. aluminum, zinc, and iron. are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary. secondary. or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine. trimethylamine. ethylamine, dibutylamine.triisopropylamine, N-methylhexylamine, deeylamine, dodecylamine,allylamine, crotylamine. cyclopentylamine, dicyclohexylamine,benzylamine. dibenzylamine, a-phenylethylamine. B-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic.and araliphatic amines containing up to and including about 18 carbonatoms, as

-well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine,piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, 4- ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrrolidine, l,4-dimethylpiperazine, 2-

methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydropholic groups, e.g., mono-. di-, andtriethanolamine, ethyldiethanolamine, N-butylethanolamine.2-amino-l-butanol, 2-amino-2- ethyl-1,3-propanediol, 2-amino-2-methyll-propanol,

tris(hydroxymethyl)aminomethane, N- phenylethanolamine.N-(p-tcrt-amylphenyl)diethanolamine, galactamine, N-methylgulcamine, N-methylglucosamine, ephedrine, phenylcphrine. epimephrinc, procaine. andthe like.

Examples of suitable pharamcologically acceptable quaternary ammoniumcations are tetramethylammonium. tetramethylammonium.tetraethylammonium, benzyltrimcthylammonium, phenyltriethylammonium, andthe like.

As discussed above, the compounds of formulas Vllle to Xle areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally.buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For the purpose, it is preferred because ofincreased water solubility that R in the formula Vllle to Xle compoundbe hydrogen or a pharmacologically acceptable cation. For subcutaneousor intramuscular injection, sterile solutions or suspensions of theacid, salt, or ester form in aqueous or non-aqueous media are used.Tablets, capsules, and liquid preparations such as syrups, elixers, andsimple solutions, with the usual pharmaceutical carriers are used fororal or sublingual administration. For rectal or vaginal administration,suppositories prepared known in the art are used. For tissue implants, astcrile tablet or silicone rubber capsule or other object containing orimpregnated with the substance is used.

Racemic PGF racemic PGF racemic PGF B racemic PGA racemic P08 and theother compounds encompassed by formulas Vllle, IXe, Xe, and Xle areproduced by the reactions and procedures described hereinafter. Asintermediates there are produced the corresponding5,6,17,1S-dehydroprostaglandins Vllld, lXd, Xd, and Xld which in thefree acid or salt forms are useful also for the purposes given above,The enantiomorphs of the V111, IX, X, and XI compounds are formed eitherby resolution of the final product racemate or a racemic intermediate.

Racemic PGF racemic PGF B and the other PGF -type compounds encompassedby formula IX are prepared by carbonyl reduction of the correspondingPGE -type compounds encompassed by formula Vlll. For example, carbonylreduction of racemic PGE V1- lle, gives a mixture of racemic PGF lXea,and racemic PGF B lXeB. The corresponding 5,6,17,18- dehydro PGF -typecompounds, lXd, are produced in a like manner from 5,6,17,18-dehydro-PGF-type compounds, Vllld, and by hydrogenation of the acetylenic bonds areconverted to the corresponding PGF -type compounds, lXe.

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example,

- Bergstrom et al., Arkiv Kemi, 19,563 (1963 and Acta Chem. Scand. 16,969 (1962), and British Specification No. 1,097,533. Any reducing agentis used which does not react with carbon-carbon double bonds or estergroups. Preferred reagents are lithium (tri-tertbutoxy) aluminum hydrideand the metal borohydrides, especially sodium, potassium and zincborohydrides. The mixtures of alpha and beta hydroxy reduction productsare separated into the individual alpha and beta isomers by methodsknown in the art for the separation of analogous pairs of known isomericprostanoic acid derivatives. See, for example, Bergstrom et al., citedabove, Granstrom et al., J. Biol. Chem. 240, 457 (1965), and Green etal., J. Lipid Research, 5, 117 1964). Especially preferred as separationmethods are partition chromatographic procedures, both normal andreversed phase, preparative thin layer chromatography, andcountercurrent distribution procedures. They can be applied eitherbefore or after the hydrogenation of the acetylenic bonds.

Racemic PGA and other PGA -type compounds encompassed by formula X areprepared by acidic dehydration of the corresponding PGE -type compoundsencompassed by formula Vlll. For example, acidic dehydration of racemicPGE Vllle, gives racemic PGA Xe. The corresponding 5,6,17,l8-dehydro-PGA-type compounds Xd, are produced in a like manner from5,6.l7,l8-dehydro-PGE -type compounds, Vllld, and by hydrogenation ofthe acetylenic bonds are converted to PGA -type compounds, Xe.

These acidicv dehydrations are carried out by methods known in the artfor acidic dehydration of known prostanoic acid derivatives. See, forexample, Pike et al., Proc. Nobel Symposium 11, Stockholm (1966),Interscience Publishers, New York, p. 161 (1967); and BritishSpecification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms,inclusive, especially acetic acid, are preferred acids for this acidicdehydration. They can be applied either before or after thehydrogenation of the acetylenic bonds.

Racemic PGB and the other compounds encompassed by formula Xle areprepared by basic dehydration of the corresponding PGE -type compoundsencompassed by formula Vllle or by contacting the corresponding PGA-type compounds encompassed by formula Xe with base. For example, bothracemic PGE Vllle, and racemic PGA Xe, give racemic PGB Xle, ontreatment with base. Presumably the base first causes dehydration of thePGE to PGA and then causes the ring double bond of PGA to migrate to anew position. The corresponding 5,6,17,18-dehydro- PGB -type compounds,Xld, are produced in a like manner from 5,6,l7,18-dehydro-PGE Vllld, or5,6,17,l8-dehydro-PGA -type compounds, Xd, and by hydrogenation of theacetylenie bonds are converted to PGB -type compounds, Xld.

These basic dehydration and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., .1. Biol. Chem. 238,3555 1963). The base is any whose aqueous solution has pH greater than10. Preferred bases are the alkali metal hydroxides. A mixture of waterand sufficient of a watermiscible alkanol to give a homogeneous reactionmixture is suitable as a reaction medium. The PGE -type or PGA -typecompound is maintained in such a reaction medium until no further PGB-type compound is formed, as shown by the characteristic ultravioletlight absorption for the PGB -type compound. They can be applied eitherbefore or after the hydrogenation of the acetylenic bonds.

These various transformations of the PGE -type compounds of formulaVllle to the PGF -type, lXe, PGA type, Xe, and PGB -type, Xle, compoundsare shown in Chart A, wherein R R R R.,, A, and are as defined above.The same transformation can be applied to the 5,6,17,18-dehydro-PGE-type compounds, Vl-

IId, as shown in Chart A-l. If desired. the 5,6,17,18- dehydro-PGA -typecompounds, Xd, can be converted to PGA -type compounds. Xe, byhydrogenation by the procedures of step 8 and 8a, infra.

CHART A CHART C Br-A-CH OH XXI ar-A-cuao l: j xx l HO-CHa-CECH HaI-CH-CEC-A-CH OQ XVII I CHART u S 7/ KL 0L 5 b 1:: a te 7 P I XXV P 0I-EC-A-COOR C CH -CEC-A-COOR;

and R 1 =6 4 o R c H c c R H/ =C c 0H a 2 R3 cram-c 032 VI I Id I I XdCHQ'C: C-A-COOR;

Step 8a 7 Step 8b ?R4-IiR3-CnHzn-C =EC-Rg 0H 0L XXVI H H H H o c=c Q c=cCH A-COIJR; v CH A-C00R and c=c oH H H c=c 10H H ,H H0 H c=c ,c=c

a n zn 2 R cnllzn R VI l Ie Xe The bicyclic compound of formula XII inChart B is tures thereof are used as reactants according to this intheinitial reactant in these multi-step processes. It ex- 65 vention toproduce substantially the same final PGE ists in two isomeric forms, exoand cndo with respect type or 5,6,17,l8-dehydro-PGE -type productmixture.

to the attachment of the CR,,O moiety. It also exists In Belgian Pat.No. 702,477; reprinted in Farmdoc in two isomeric forms with respect tothe attachment of Complete Specifications, Book 714, No. 30.905 page thetetrahydropyranyloxy group making in all four iso- 313. Mar. 12, I968.the reaction sequence loading to meric forms. Each of those isomersseparately or mixexo form of compound XII is as follows: The hydroxy of3-cyclopentenol is protected, for example, with a tetrahydropyranylgroup. Then a diazoacetic acid ester is added to the double bond to givean exo-endo mixture of a bicyclo[3.l.O]-hexane substituted at 3 with theprotected hydroxy and at 6 with an esterified carboxyl. The exo-endomixture is treated with a base to isomerize the endo isomer in themixture to more of the exo isomer. Next, the carboxylate ester group at6 is transformed to an aldehyde group or ketone group,

..C=O, wherein R is as defined above.

In the first step of the process (Chart B), the aldehyde group or ketogroup is transformed by the Wittig reaction to a moiety of the formulaCR,=CR C,,H- -C i C-R which is in exo configuration relative to thebicyclo ring structure, and is the same as shown in formula XIII. Instep 2, the protective group is removed to regenerate the 3-hydroxy(XIV) which is then oxidized in step 3, for example, by the Jonesreagent, to give the exo compound XV Separation of the cis-exo andtrans-exo isomers of XV can be effected by the procedures described insaid Belgian patent. However, as mentioned above, that separation isusually not necessary since the cis-trans mixture is useful as areactant in the next process step.

The process described in said Belgian pat. No. 702,477 for producing theexo form of bicyclic compound XII uses as an intermediate, the exo formof a bicyclol3. l .OI-hexane substituted at 3 with a protected hydroxy,e.g., tetrahydropyranyloxy and at 6 with an esterified carboxyl. Whenthe corresponding endo compound is substituted for that exointermediate,the Belgian patent process leads to the endo form of bicyclic compoundXII. That endo intermediate used in the Belgian patent process has theformula:

COOCHs Compound XXVII is prepared by reactingendobicyclo-[3.1.0]hex-2-ene-6-carboxylic acid methyl ester withdiborane in a mixture of tetrahydrofuran and diethyl ether, a reactiongenerally known in the art, to giveendobicyclo[3.1.0]hexan-3-ol-6-carboxylic acid methyl ester which isthen reacted with dihydropyran in the presence of a catalytic amount ofPOCl to give the desired compound. This is then used as described insaid Belgian patent to produce the endo form of bicyclic compound XII.

Using this endo form of bicyclic compound XII as the starting material,steps 2 and 3 produce mixtures of endo-eis and endo-trans. These can beseparated as described for the separation of exo-cis and exo-trans XV,but this separation is usually not necessary since, as mentioned above,the cis-trans mixture is useful as a reactant in the next process step.I I

In the Wittig reaction, (Step I), the other starting compound is anorganic chloride or bromide, or iodide of the formula This can beprepared from the corresponding alcohol HO- CHR,-,C,,H ,,-C i C--R XXIXby processes already known in the art, for example, by reacting compoundXXIX with triphenylphosphine and N-bromosuccinimide.

Acetylenic alcohols of formula XXIX are generally known in the art, forexample, 3-pentyn-l-ol, 3-hexynl-ol, 4-hexynl -ol, 2-methyl-3-pentyn-I-ol, 2,3-dimethyl-4-pentyn-l-ol, 6-0ctyn-l-ol, 6-nonyn-1- ol,4-undccyn-lol, 6-dodecyn-I-ol, S-tetradecyn-I-ol, and the like. Otherswhere R, is methyl, ethyl. propyl, butyl, or the isomers thereof can bemade by reacting an acetylenic aldehyde of the formula O=CHC,,H ,,C iC--R xxx with the appropriate Grignard reagent, BrMgR These acetylenicaldehydes can be made by oxidizing the corresponding alcohol, forexample, those listed above, with a Jones reagent, Collins reagent, aMoffatt oxidation or the like. The aldehyde is then reacted with BrMgRto prepare acetylenic alcohols of formula XXIX. Compounds thusobtainable include 4-hexyn-2- ol, 4-heptyn-2-ol, 5-heptyn-2-ol,3-methyl-4-hexyn-2- ol, 3,4-dimethyl-5-hexyn-2-ol, 7-nonyn-2-ol,7-decyn- 2-ol, 5-dodecyn-2-ol, 7-tridecyn-2-ol, 5-heptyn-3ol,5-octyn-3-ol, 6-octyn-3-ol, 8-undecyn-3-ol, 6-tridecyn- 3-ol,8-tetradecyn-3-ol, and the like. Still other alkyn-lols according toformula XXIX (R hydrogen) can be made by condensing anomega-alkyl-l-olof the formula with an alkyl halide, HalR using lithium and ammonia asthe condensing agent; still others by condensing a protected halohydrinof the formula o-CHzcnH n-Hal XXXII with a l-alkyn, I-IC CR Againlithium and ammonia can be used as the condensing agent.

The protective tetrahydropyranyl group can then be removed by acidhydrolysis to form an acetylenic alcohol of formula XXIX. The latterprocess is particularly useful where R is a halo substituted alkyl. Thel-alkyn, HC CR can be made by condensing acetylene with or sodiumacetylide with an alkyl halide, R I-Ial where R is given above.

The transformation of bicyclo-ketone-olefin XXIII to glycol XXIV (Step5, Chart B) is carried out by reacting olefin XXIII with a hydroxylationreagent. Hydroxylation reagents and procedures for this purpose areknown in the art. See, for example, Gunstone, Advances in OrganicChemistry, Vol. 1, pp. 103-147, Interscience Publishers, New York, N.Y.(I960). Various isomeric glycols are obtained depending .on whetherolefin XXIII is cis or trans and endo or exo, and on whether a cis or atrans hydroxylation reagent is used. Thus endo-cis olefin XXIII gives amixture of two isomeric erythro glycols of formula XXIV with a eishydroxylation agent, e.g., potassium permanganate. The endo-cis olefinsand the endo-trans olefms XXIII give similar mixtures of two threoisomers with cis and trans hydroxylation reagents. respectively. Thesevarious glycol mixtures are separated into individual isomers by silicagel chromatography. However. this separation is usually not necessary.since each isomeric erythro glycol and each isomeric threo glycol isuseful as an intermediate according to this invention and the processesoutlined in Charts B, C, and D to produce final products of formulasVIIIe and Xe, and then, according to Chart A. to produce the other finalproducts ofthis invention. Thus the various isomeric glycol mixturesencompassed by formula XXIV produced from the various isomeric olefinsencompassed by formula XXIII are all useful for these same purposes.

In step 4 the other starting material is a haloalkynoic ester of theformula Ha1- CH C ii (A-COOR XXXIII wherein Hal is chlorine. bromine. oriodine. In effecting this step any of the alkylation procedures known inthe art to be useful for alkylating cyclic ketones with alkyl halides,especially haloalkynoic esters. can be used for the transformation of XVto XXIII. See. for example, the above mentioned Belgian Pat. No. 702,477for procedures useful here and used there to carry out similaralkylations.

For this alkylation, it is preferred that Hal be bromo, or iodo. Any ofthe usual alkylation bases, e.g., alkali metal alkoxides, alkali metalamides. and alkali metal hydrides, are useful for this alkylation.Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodiumand potassium are preferred alkali metals. Especially preferred ispotassium tert-butoxide. Preferred diluents for this alkylation aretetrahydrofuran and 1,2- dimethoxyethane. Otherwise, procedures forproducing and isolating the desired formula XXIII compound are withinthe skill of the art.

This alkylation procedure produces a mixture of alpha and betaalkylation products, i.e., a mixture of formula XXIII products whereinpart has the CH C I CACOOR moiety attached in alpha configuration andwherein part has that moiety attached in beta configuration. When aboutone equivalent of base per equivalent of formula XV ketone is used, thealpha configuration usually predominates. Use of an excess of base andlonger reaction times usually result in production of larger amounts ofbeta products. These alphabeta isomer mixtures are separated at thisstage or at any subsequent stage in the multi-step processes shown inCharts B and D. Silica gel chromatography is preferred for thisseparation.

An alternative alkylation procedure is shown in steps 4a, 4b, and 4c.The alkylating agent XVII is reacted with the bicyclo-ketone-olefin XVby the alkylation procedure described above for step 4.

The alkylating agent of formula XVII is prepared by the series ofreactions shown in Chart C. The initial reactants. BrACI-I OH, are omegabromoalcohols which are known in the art or can be prepared by methodsknown in the art. For example, when A in the final product is to betrimethylene as it is in racemic PGE the necessary 4-bromobutanol isprepared by reacting tetrahydrofuran with hydrogen bromide.

To illustrate the availability of the other bromoglycols of formula XXI(Chart C). consider the abovedescribed special compounds of formulaVIIle. wherein A is -(CH ),,Z. wherein his zero. one. 2, or 3, and Z isethylene substituted by one or 2-fluoro. methyl. or ethyl, or by onealkyl of 3 or 4 carbon atoms. These omega-bromoalcohols. Br(CH ),,Z-CHOH. are prepared by starting with the appropriate succinic acid.HOOCZ-COOH. all of which are known or easily accessible by knownmethods. These succinic acids are transformed to the correspondinganhydrides by known procedures. Each anhydride is then reacted with analkanol, for example. methanol, to give the corresponding succinic acidhalf ester. e.g., HOOCZ- COOCH When Z is unsymmetrical, e.g.,substituted with one fluoro, a mixture of isomeric half esters isobtained, HOOCZCOOCH and CH -OOCZ-- COOH, which is separated to give thedesired isomer.

When it is desired that h is Br-(CH -ZCH OH be zero. the succinic acidhalf ester is subjected to the Hunsdiecker reaction. thereby producingBrZ- COOCH which is reduced by lithium aluminum hydride to BrZ-CH OH.When 11 is to be one. the earboxyl group of the succinic acid half esteris changed to acid chloride with thionyl chloride, to aldehyde by theRosenmund reduction, to alcohol with sodium borohydride, and to CH Brwith PBr giving BRCH- ZCOOCH which is then reduced to BrCH- -ZCH OI-Iwith lithium aluminum hydride. When 17 is to be 2 or 3, the succinicacid half ester is subjected once or twice to the Arndt-Eistert reactionto produce HOOCCI-I ZCOOCH or HOCCCH C- H ZCOOCH which is then subjectedto the same series of reactions given above to give BrCH C- H Z-CI-IOI-I or BrCH CH CH -Z-CH OH.

Referring again to Chart C, the several process steps, XXI to XX, XX toXIX, XIX to XVIII, and XVIII to XVII are exemplified in Belgian PatentSer. No. 747,348, Sept. 14, 1970, in the case wherein A is trimethylene.Those procedures are used when A is other than trimethylene and withinthe scope of A as defined above.

The transformation of alkylation product XVI to primary alcohol XXII(Chart B) is carried out by acid catalyzed hydrolysis of thetetrahydropyranyl ether XVI. Such hydrolysis of tetrahydropyranyl ethersis well known to those skilled in the art. Oxalic acid is especiallypreferred for this acid hydrolysis of XVI to XXII.

The oxidation of primary alcohol XXII to carboxylic acid XXIII (Chart B,R H) is carried out by oxidizing XXII with any oxidizing agent whichwill not also attack the acetylenic linkage in XXII. An especiallyuseful reagent for this purpose is the Jones reagent, i.e., acidicchromic acid. See J. Chem. Soc. 39 (1946). Acetone is a suitable diluentfor this purpose, and a slight excess of oxidant and temperatures atleast as low as about 0 C., preferably about lO to about 20 C. should beused. The oxidation proceeds rapidly and is usually complete in about 5to about 30 minutes. Excess oxidant is destroyed, for example, byaddition of a lower alkanol, advantageously isopropyl alcohol, and thealdehyde is isolated by conventional methods, for example, by extractionwith a suitable solvent, e.g., diethyl ether. Other oxidizing agents canalso be used. Examples are mixtures of chromium trioxide and pyridine ormixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide. See, forexample, J. Am. Chem. Soc. 87.5661 (1965).

The acid thus formed (compound XXIII, R H) can then be esterified byprocedures already known in the art for transforming carboxylic acids toesters. For example. a diazohydrocarbon, e.g., diazomethane,advantageously in diethyl ether solution, is reacted with the acid toproduce the ester, e.g., the methyl ester, by known procedures. When Ris ethyl substituted with .3-chloro. 2 or 3 bromo, or I, 2, or 3 iodo,the acid is reacted with the appropriate haloethanol, e.g., B, B,B-trichloroethanol, in the presence of a carbodiimide, e.g.,dicyclohexylcarbodiimide, and a base, e.g., pyridine. This mixture,advantageously with an inert dilucnt. e.g., dichloromethane, usuallyproduces the desired haloethyl ester within several hours at about 25 C.The other esters within the scope of R are prepared by procedures knownto the art.

In step 6 the vicinal hydroxy groups of the glycol XXIV are modified byreplacing the hydrogens with an alkanesulfonyl leaving-group, L, forexample mesyl. containing up to and including 5 carbon atoms. Thus, thebisalkanesulfonic acid esters XXV (Chart B) are prepared by reactingglycol XXIV with an alkylsulfonyl chloride or bromide, or with analkanesulfonic acid anhydride. Alkylsulfonyl chlorides are preferred forthis reaction. The reaction is carried out in the presence of a base toneutralize the by-product acid. Especially suitable bases are tertiaryamines, e.g., dimethylaniline or pyridine. It is usually sufficientmerely to mix the two reactants and the base, and maintain the mixturein the range to 25 C. for several hours. The formula XXVbis-alkanesulfonic acid esters are then isolated by procedures known tothe art.

The transformation in Chart D, Step 7a, of the modified glycol XXV toVIIId is carried out by reacting XXV with water in the range of about 0to about 60 C. The resulting product is raeemic 5,6,17,18-dehydro- PGEor an analog thereof. In making racemic 5,6,l7,l8-dehydro-PGE usually 25C. is a suitable reaction temperature, the reaction then proceeding to.completion in about to 10 hours. It is advantageous to have a homogenousreaction mixture. This is accomplished by adding sufficient of awater-soluble organic diluent which does not enter into the reaction.Acetone is a suitable diluent. The desired product is isolated byevaporation of excess water and diluent if one is used. The residuecontains a mixture of formula VIIId isomers which differ in theconfiguration of the side chain hydroxy, that being either R or S. Theseare separated from by-products and from each other by silica gelchromatography. A usual by-product is the monosulfonic acid ester offormula XXVI (Chart D). This mono-sulfonic acid ester is esterified tothe formula XXV bis-sulfonic acid ester in the same manner describedabove for the transformation of glycol XXIV to bis-ester XXV, and thusis recycled in step 7a.

For the transformation of bis-esters XXV to the formula VIIId products,it is preferred to use the bis-mesyl esters, i.e., compounds XXV whereinL is mesyl.

In step 8a the acetylenic linkages are hydrogenated to olefiniclinkages. A suitable method is to hydrogenate over a Lindlar catalyst inthe presence of quinoline. The Lindlar catalyst is Spercent palladium-onbarium sulfate. Methanol or like inert solvent or diluent is used andthe pressure is low, advantageously slightly above atmospheric andordinarily not above about two atmospheres. The resulting products canbe isolated by silica gel chromatography. If the starting materialcontains both the R and S epimers, the product VIIIe will also containthe R and S epimers. These also can be separated by silica gelchromatography. As shown on Chart D, the hydrogenation of VIIId (of Xd)leads to PG -type compounds depending on whether the acetylenic bonds ofVIIId (or Xd) are reduced to cis-CH=CH. The above describedhydrogenation gives this type of reduction of the acetylenic bonds.

The transformation of the protected glycols XXV (Step 7b) to5,6,17,l8-dehydr0-PGA -type compounds (Xd) is carried out by heating theformula XXV bisester in the range 40 to C. with a combination of water,a base characterized by its water solution having a pH 8 to 12, andsufficient inert water-soluble organic diluent to form a basic andsubstantially homogenous reaction mixture. A reaction time of one to 10hours is usually used. Preferred bases are the water-soluble salts ofcarbonic acid, especially alkali metal bicarbonates, e.g., sodiumbicarbonate. A suitable diluent is actone. The products are isolated andseparated as described above for step 7a and hydrogenated as in step 8a.The same mono-sulfonic acid esters XXVI observed as byproducts in step7a are also observed in step 7b. Also, in step 7b the bis-mesyl estersXXV are preferred. Also as in steps 7a and 8a, during production of Xdand Xe, alpha XXV gives alpha Xd and alp;ha Xe, beta XXV gives beta Xdand beta Xe, and in each case, alpha and beta Xd and Xe, a mixture of Rand S isomers is obtained. These R and S isomer mixtures are separatedby silica gel chromatography.

The configuration of the CI-I -C- i CA-COOR moiety does not changeduring these transformations of Charts B and D. Also the configurationdoes not change in hydrogenation. Therefore, when the CI-I C CACOOR isattached initially in alpha configuration racemic 5,6,17,18- dehydro-PGE-type, VIIId, PGE -type, VIIIe, 5,6,17,l8-dehydro-PGA -type, Xd, and PGA-type, Xe, compounds are obtained, and when the moiety is attached inbeta configuration, the 8-isoforms are obtained.

Resolution of the final product racemates or the racemic intermediatesare carried out by procedures known in the art. For example, when afinal compound of formula VIIIe, IXe, Xe, or XIe is a free acid, the dlform (racemate) thereof is resolved into the d and 1 forms (the naturaland unnatural configurations) by reacting said free acid by knowngeneral procedures with an optically active base, e.g., brucine orstrychnine, to give a mixture of two diastereoisomers which areseparated by known general procedures, e.g., fractional crystallization,to ,give the separate diastereoisomeric salts. The optically active acidof formula VIII to XI is then obtained by treatment of the salt with anacid by known general procedures. Alternatively, the free acid form ofthe intermediate dehydro compounds VIIId, IXd, Xd, or XId is resolvedinto separate d and 1 forms and then esterified and transformed furtherto the corresponding optically active form of the final product VIIIe toXIe as described above.

Alternatively, glycol reactant XXIV. in exo or endo form, is transformedto a ketal with an optically active l,2-glycol, e.g.,D-(-)-2,3-butanediol, by reaction of said 1,2-glycol with the formulaXXIV compound in the presence of a strong acid, e.g., p-toluenesulfonicacid. The resulting ketal is a mixture of a diasteroisomers which isseparated into the d and l diastereoisomers, each of which is thenhydrolyzed with an acid, e.g., oxalic acid, to the original ketocompound, now in optically active form. These reactions involvingoptically active glycols for resolution purposes are generally known inthe art. See, for example, Chem. Ind. 1664 (196i and J. Am. Chem. Soc.84, 2938 (1962). Dithiols may be used instead of glycols.

The novel PGE PGF PGA and PGB -type compounds of formula Vllle to Xlewherein R is alkyl of one to 4 carbon atoms, inclusive; preferablymethyl or ethyl, are preferred over the corresponding PGE PGF PGA- andPGB -type compounds in which R is hydrogen for the above-describedpharmacological purposes. For convenience the compounds of the inventionwhere R is alkyl will be referred to as l5-alkyl analogs even though thenumber actually will be greater or less than depending on whether thenumber of methylene groups in A is greater or less than three.

These l5-alkyl prostaglandin analogs are surprisingly and unexpectedlymore useful than the corresponding l5-hydrogen compounds for the reasonthat they are substantially more specific with regard to potency incausing prostaglandin-like biological responses, and have asubstantially longer duration of biological activ ity. For that reason,fewer and smaller doses of these l5alkyl prostaglandin analogs areneeded to attain the desired pharmacological results. I

Although the above-mentioned l5-alkyl compounds are produced by themethods outlined above in Charts A-D, the preferred methods are setforth in Charts E and F as follows.

CHART E HO v CHz-Q-ACOOR;

Ho a; CnHan-Q-R (Oxidation) o v CH -Q-ACOOR R4, Vl I la H0, H/ =C c OHa; n zn-Q- a CHART F HbH l(oxidation) l(silylation) epimers of both ofthose, i.e., wherein the configuration at C-l5 is R rather than S asshown. Also in Chart E,

A, R,, R and R are as defined above, R is alkyl of one to 4 carbonatoms, and both Qs are ethynylene or cis-ethylene For thetransformations of chart E, the B-hydroxy isomers of reactant IXa aresuitable starting materials when the carboxyl side chain is alpha,although the corresponding a-hydroxy isomers are also useful for thispurpose.

Oxidation reagents useful for the-transformation set forth in Chart Eare known to the art. An especially useful reagent for this purpose isthe Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39(1946). Acetone is a suitable diluent for this purpose, and a slightexcess beyond the amount necessary to oxidize one of thesecondaryhydroxy groups of the formula IXa reactant is used. Reactiontemperature at least as low as about C. should be used. Preferredreaction temperatures are in the range l0 to 50 C. The oxidationproceeds rapidly and is usually complete in about to minutes. The excessoxidant is destroyed, for example by addition of a lower alkanol,advantageously, isopropyl alcohol, and the formula Villa PGE- typeproduct is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart Etransformations are silver carbonate on diatomite [Chem. Commun. 1 102(1969)], mixtures of chromium trioxide and pyridine [Tetrahedron Letters3363 (1968, J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351(1962)], mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide[J. Am. Chem. Soc. 89, 5505 (1967)], and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide [.I. Am. Chem. Soc.87,5661 (1965)].

The novel 15-alkyl PGF and PGF -type acids and esters of formula IXa arepreferably prepared from the corresponding IS-hydrogen compounds by thesequence of transformations shown in Chart F, wherein formulas IX,XXXVII, XXXVIII, IXa(S), and IXa(R) include optically active compoundsas shown and racemic compounds of those formulas and the mirror imagesthereof. Also in Chart F, R is alkyl of one to 4 carbon atoms,inclusive, and A, R R R are as heretofore defined and Q is ethynylene orcis-ethylene. Also in Chart F, G is alkyl of one to 4 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbonatoms, inclusive, and R is alkyl or silyl of the formula -Si-(G) whereinG is as defined above. The various Gs of a -Si(G) moiety are alike ordifferent. For example, a -Si(G) can be trimethylsilyl,dimethylphenylsilyl, or methylphenylbenzylsilyl. Examples of alkyl ofone to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl. Examples of aralkyl of 7 to12 carbon atoms, inclusive, are benzyl, phenethyl, a-phenylethyl,3-phenylpropyl, a-naphthylmethyl, and 2-(B-naphthyl)ethyl. Examples ofphenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4carbon atoms, inclusive, are p-chlorophenyl, m-fluorophenyl, I

o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3- methylphenyl.

In Chart F, the final PGF and PGF B -type products are those encompassedby formulas IXa(S) and IXa(R), respectively, where both Qs arecis-ethylene.

The heretofore-described acids and estersof formula IX are transformedto .the corresponding intermediate l5-oxo acids and esters of formulaXXXVII, by oxidal,4-benzoquinone, activated manganese dioxide, or nickelperoxide (see Fieser et al., Reagents for Organic Synthesis," John Wiley& Sons, Inc., New York, N.Y., pp. 215, 637, and 73]). Alternatively,these oxidations are carried out by oxygenation in the presence of theIS-hydroxyprostaglandin dehydrogenase of swine lung [see Arkiv foer Kemi25, 293 (1966)]. These reagents are used according to procedures knownin the art. See, for example, J. Biol. Chem. 239, 4097 (1964).

The novel 5,6,l7,18-dehydro-PGF -type compounds of formula IXa areobtained by the borohydride reduction of the corresponding5,6,l7,18-dehydro-PGE type compounds of formula VIIIa. Here again thenumbering is merely typical and will vary according to the values of Aand n.

Referring again to Chart F, the intermediate compounds of formula XXXVIIare transformed to silyl derivatives of formula XXXVIII by proceduresknown in the art. See, for example, Pierce, Silylation of OrganicCompounds, Pierce Chemical Co., Rockford, Ill. (1968). Both hydroxygroups of the formula XXXVII reactants are thereby transformed toO--Si--(G) moieties wherein G is as defined above, and sufficient of thesilylating agent is used for that purpose according to known procedures.When R, is the formula XXXVII intermediate is hydrogen, the -COOH moietythereby defined is simultaneously transformed to COOSi-(G) additionalsilylating agent being used for this purpose. This latter transformationis aided by excess silylating agent and prolonged treatment. When R, informula XXXVII is alkyl, then R in formula XXXVII] will also be alkyl.The necessary silylating agents for these transformations are known inthe art or are prepared by methods known in the art. See, for example,Post, Silicones and Other Organic Silicon Compounds, Reinhold PublishingCorp., New York, N.Y. (1949).

Referring again to Chart F the intermediate silyl compounds of theformula XXXVIII are transformed to the final compounds of formulasIXa(S) and IXa(R) by first reacting the'silyl compound with a Grignardreagent of the formula R Mgl-lal wherein R is as defined above, and Halis chloro, bromo, or iodo. For this purpose, it is preferred that Hal bebromo. This reaction is carried out by the usual procedure for Grignardreactions, using diethyl ether as a reaction solvent and saturatedaqueous ammonium chloride solution to hydrolyze the Grignard complex.The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzedwith water to remove the silyl groups. For this purpose, it isadvantageous to use a mixture of water and sufficient of awater-miscible solvent, e.g., ethanol to give a homogenous reactionmixture. The hydrolysis is usually complete in 2 to 6 hours at 25C., andis preferably carried out in an atmosphere of an inert gas, e.g.,nitrogen or argon.

The mixture of 15-8 and 15-R isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair of 15-8 and 15-R isomersare more readily separated by silica gel chromatography than are thecorresponding acids. In those cases, it is advantageous to .esterify themixture of acids, separate the two esters, and then, if desired,saponify the esters by procedures known in the art and described herein.

The novel 15-alkyl PGA-type acids and esters of formula Xa are preparedfrom the IS-alkyl PGE compounds, Villa, heretofore described, bydehydration as shown in Chart G. For this purpose. a dehydrating agentis used which removes the hydroxy group from the alicyclic ring in thepresence of a hydroxy group on a tertiary carbon atoms. Formula Villaincludes optically active compounds as shown and racemic compounds ofthat formula and the mirror images thereof, and also the lS-epimers ofboth of those, i.e., wherein the configuration at 015 is R or S and thatof the carboxyl side chain is a or B.

Dehydration agents useful for the transformation to PGA -type compoundsset forth in Chart G are known in the art. Any of the knownsubstantially neutral dehydrating CHART G CHa-Q-A-COOR CH -Q-A-COOR;

agents is used for these reactions. See Fieser et al., -Reagents forOrganic Syntheses, John Wiley .& Sons, Inc., New York, 1967. Preferreddehydrating agents are mixtures of at least an equivalent amount of acarbodiimide and a catalytic amount of a copper (ll) salt. Especiallypreferred are mixtures of at least an equivalent amount ofdicyclohexylcarbodiimide and a catalytic amount of copper (ll) chloride.An equivalent amount of a carbodiimide means one mole of thecarbodiimide for each mole of the Formula-Villa reactant. To ensurecompleteness of the reaction, it is advanta geous to use an excess ofthe carbodiimide, i.e., 1.5 to 5 or even more equivalents of thecarbodiimide.

The dehydration is advantageously carried out in the presence of aninert organic diluent which gives a homogeneous reaction mixture withrespect to the Formula-Vllla reactant and the carbodiimide. Diethylether is a suitable diluent.

It is advantageous to carry out the dehydration in an atmosphere of aninert gas, e.g., nitrogen, helium, or argon.

The time required for the dehydration will depend in part on thereaction temperature. With the reaction temperature in the range 20 to30 C., the dehydration usually takes place in about 40 to hours.

The Formula-Xa product is isolated by methods known in the art, e.g.,filtration of the reaction mixture and evaporation of the filtrate. Theproduct is then purified by methods known in the art, advantageously bychromatography on silica gel.

The conversion of Formula-Villa and Formula-Xa compounds to Formula Xlacompounds is effected with base as described above in connection withCharts A and A-l.

The formula VIII and X compounds produced according to the processesoutlined in Charts B, C, and D and discussed above are all carboxylicacid esters, wherein R is not hydrogen. Moreover, when these compoundsare used to produce compounds of formulas IX and XI according to theprocesses outlined in Chart A and discussed above, corresponding Resters are likely to be produced, especially in the case of the POP},compounds of formulas IX. For some of the uses described above, it ispreferred that these formula VIII to XI compounds be in free acid form,or in salt form which requires the free acid as a starting material. Itis also sometimes desirable to have the free acid or salt forms of theacetylenic compounds of the 5,6,17,18- dehydro-PGE -type (WM) and the5,6,17,18-dehydro- PGA -type (Xd) compounds, as well as the 5,6,17,18-dehydro-PGF -type (IXd) and 5,6,17,18-dehydro- PGB -type (XId) compoundsand which are derivable therefrom by the processes outlined in ChartA-l, because these free acids and salt forms have properties like thoseof the corresponding hydrogenated (olefinic) compounds and are usefulfor the same purposes detailed above.

The formula IXe, XIe, IXd, and XId R -esters are easily hydrolyzed orsaponified by the usual known procedures, especially when R is alkyl ofone to 4 carbon atoms, inclusive. Therefore it is preferred when thefree acid form of compounds IXe, Xle, IXd, and XId is desired, that R bysuch alkyl, especially methyl or ethyl.

On the other hand, the formula VlIIe, Xe, VIIld, and Xd products aredifficult to hydrolyze or saponify without unwanted structural changesin the desired acids. There are two other procedures useful to make thefree acid form of formula VIIIe, Xe, Vllld, and Xd products.

One of those procedures, is applicable mainly in preparing the freeacids from the corresponding alkyl esters wherein the alkyl groupcontains one to 8 carbon atoms, inclusive. That procedure comprisessubjecting the alkyl ester corresponding to formula VIIIe, Xe, VI- IId,or Xd to the acylase enzyme system of a microorganism species ofSubphylum 2 of Phylum III, and thereafter isolating the acid. Especiallypreferred for this purpose are species of the orders Mucorales,Hypocreales, Moniliales, and Actinomycetales. Also especially preferredfor this purpose are the species of the families Mucoraceae,Cunninghamellaceae, Nectrcaceae, Moniliaceae, Dematiaceae,Tuberculariaceae. Actinomycetaceae, and Streptomycetaceae. Alsoespecially preferred for this purpose are species of the genera Absidia,Circinella, Gongronella, Rhizopus, Cunninghamella, Calconectria,Aspergillus, Penicillium, Sporotrichum, Cladosporium, Fusarium,Nocardia, and Streptomyces.

Examples of microorganisms falling within the scope of those preferredorders, families, and genera are listed in U.S. Pat. No. 3,290,226 anddetails of the process are disclosed in German Offenlegunsschift No.1,937,678, reprinted in Farmdoc Complete Specifications, Book No. 13,No. 6863R, Week R5, March 18,

This enzymatic ester hydrolysis is carried out by shaking the formulaVIIIe, Xe, Vllld, or Xd alkyl ester in aqueous suspension with theenzyme contained in a culture of one of the above-mentionedmicroorganism species until the ester is hydrolyzed. A reactiontemperature in the range 20 to 30 C. is usually satisfactory. A reactiontime of one to 20 hours is usually sufficient to obtain the desiredhydrolysis. Exclusion of air from the reaction mixture, for example,with argon or nitrogen is usually desirable.

The enzyme is obtained by harvest of cells from the culture, followed bywashing and resuspension of the cells in water, and cell disintegration,for example, by stirring with glass beads or by sonic or ultrasonicvibrations. The entire aqueous disintegration mixture is used as asource of the enzyme. Alternatively and preferably, however, thecellular debris is removed by centrifugation or filtration, and theaqueous supernatant or filtrate is used.

In some cases, it is advantageous to grow the microorganism culture inthe presence of an alkyl ester of an aliphatic acid, said acidcontaining 10 to carbon atoms, inclusive, and said alkyl containing oneto 8 carbon atoms, inclusive, or to add such an ester to the culture andmaintain the culture without additional growth for one to 24 hoursbefore cell harvest. Thereby, the enzyme produced is sometimes made moreeffective in transforming the formula VIIIe, Xe, VIIId, or Xd ester tothe free acid. An example ofa useful alkyl ester for this purpose ismethyl oleate.

Although, as mentioned above, most of the R esters encompassed byformulas Vllle, Xe, VIIId, and Xd are not easily hydrolyzed orsaponified to the corresponding free acids, certain of those esters aretransformed to free acids by another method. Those esters are thehaloethyl esters wherein R is CI-I CCI They are transformed to freeacids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbonatoms, preferably acetic acid. Zinc dust is preferred as the physicalform of the zinc. Mixing the halo ethyl ester with the zinc dust atabout 25 C. for several hours usually causes substantially completereplacement of the haloethyl moiety of the formula VIIIe, Xe, Vllld, orXd ester with hydrogen. The free acid is then isolated from the reactionmixture by procedures known to the art. This procedure is alsoapplicable to the production of the free acid form of the formula lXe,Xle, IXd, and Xld compounds from the corresponding haloethyl estersthereof.

As described above, the alkylation of cyclic ketone XV to ketone XXIII(Chart B) usually produces a mixture of alpha and beta alkylationproducts with respect to the -CH -C E CA-COOR or the moiety. Also asdescribed above, those two isomers lead to different final products,alpha leading to the 'PG -series and beta leading to the 8-iso-PG-series. If

a compound in one or the other of those series is preferred, there aretwo methods for favoring production of the preferred final product.

One of those methods involves isomerization of the final product offormula VIIIe or formula VlIId. Either the alpha isomer of formula VIIIeor Vllld, or the beta isomer of formula VIIIe or VlIId is maintained inan inert liquid diluent in the range 0 to C. and in the presence of abase characterized by its water solution having a pH below about 10until a substantial amount of the isomer has been isomerized to theother isomer, i.e., alpha to beta or beta to alpha. Preferred bases forthis purpose are the alkali metal salts of carboxylic acids, especiallyalkanoic acids of 2 to 4 carbon atoms, e.g., sodium acetate. Examples ofuseful inert liquid diluents are alkanols of one to 4 carbon atoms,e.g., ethanol. This reaction at about 25 C. takes about one to about 20days. Apparently an equilibrium is established. The mixtures of the twoisomers, alpha and beta, are separated from the reaction mixture byknown proccdures, and then the two isomers are separated from each otherby known procedures, for example, chromatography, recrystallization, ora combination of those. The less preferred isomer is then subjected=tothe same isomerization to produce more of the preferred isomer. In thismanner, by repeated isomerizations and separations, substantially all ofthe less preferred isomer of the formula VIIIe or formula VIIId compoundis transformed to more preferred isomer.

The second method for favoring production of a preferred final formulaVIIIe or formula VIIId isomer involves any one of the intermediates offormulas XVI, XXII, XXIII, XXIV, or XXV (Chart B). Either thealpha formor the beta form of one of those intermediates is transformed to amixture of both isomers by maintaining one or the other isomer, alpha,or beta, in an inert liquid diluent in the presence of a base and inrange 0 to C. until a substantial amount of the starting isomer has beenisomerizcd to the other isomer. Preferred bases for this isomerizationare alkali metal amides, alkali metal alkoxides, alkali metal hydrides,and triarylmethyl alkali metals. Especially preferred are alkali metaltert-alkoxides of 4 to 8 carbon atoms, e.g., potassium tert-butoxide.This reaction at about 25 C. proceeds rapidly tone minute to severalhours). Apparently an equilibrium mixture of both isomers is formed,starting with either isomer. The isomer mixtures in the equilibriummixture thus obtained are isolated by known procedures. and then the twoisomers are separated from each other by known procedures, for example,chromatography. The less preferred isomer is then subjected to the sameisomerization to produce more of the preferred isomer. In this manner,by repeated isomerizations and separations, substantially all of theless preferred isomer of any of these intermediates is transformed tothe more preferred isomer.

The final formula Viiie, lXe, Xe, and Xle compounds and Wild, iXd, Xd,and Xid compounds prepared by the processes of this invention, in freeacid form, are transformed to pharmacologically acceptable salts ofneutralization with appropriate amounts of the corresponding inorganicor organic base, examples of which correspond to the cations and amineslisted above. These transformations are carried out by a variety ofprocedures known in the art to be generally useful for the preparationof inorganic, i.e., metal or ammonium, salts, amine acid addition salts,and quaternary ammonium salts. The choice of procedure depends in partupon the solubility characteristics of the particular salt to beprepared. in the case of the inorganic salts, it is usually suitable todissolve the acid in water containing the stoichiometric amount of ahydroxide, carbonate, or bicarbonate corresponding to the inorganic saltdesired. For example. such use of sodium hydroxide, sodium carbonate, orsodium bicarbonate gives a solution of the sodium salt. Evaporation ofthe water or addition of a water-miscible solvent of moderate polarity,for example, a lower alkanol or a lower alkanone, gives the solidinorganic salt if that form is desired.

To produce an amine salt, the formula Ville, lXe, Xe, Xle, Viiid, IXd,Xd, or Xid acid is dissolved in a suitable solvent of either moderate orlow polarity. Examples of the .former are ethanol, acetone, and ethylacetate. Examples of the latter are diethyl ether and benzene. At leasta stoichiometric amount of the amine corresponding to the desired cationis then added to that solution. If the resulting salt does notprecipitate, it is usually obtained in solid form by addition of amiscible diluent of low polarity or by evaporation. if the amine isrelatively volatile, any excess can easily be removed by evaporation. Itis preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe formula Ville, lXe, Xe, Xle, Vliid, iXd, Xd, or Xid acid with thestoichiometric amount of the corresponding quaternary ammonium hydroxidein water solution, followed by evaporation of the water.

The invention can be more fully understood by the following examples andpreparations in which the parts are by weight and solvent ratios are byvolume unless otherwise specified.

All temperatures are in degrees centigrade.

NMR spectra are recorded on a Varian A-60 spectrophotometer ondeuterochioroform solutions with tetramethylsilane as an internalstandard (downfield).

Mass spectra are recorded on an Atlas Cl-i-4 mass spectrometer with aTO-4 source (ionization voltage 70 For convenience of the formulas aregiven in the natural configuration, it being understood, though, thatthe compounds produced, unless otherwise specified, include theenantiomorphs.

EXAMPLE 1 Racemic PGE methylester (XXXIX) 0 eaf (cage-000cm 4 I, H =c0HH/ :H xXXIX R cH CHzCHS Part A-l Endo-bicyclo[3.1.0]hexan-3-ol-6-carboxyiic acid methyl ester A mixture of endo-bicyclo[3. l.0lhex-2-ene-6- earboxylic acid methyl ester (103 g.) and anhydrousdiethyl ether (650 ml.) is stirred under nitrogen and cooled to 5 C. Aone molar solution (284 ml.) of diborane in tetrahydrofuran is addeddropwise during 30 minutes while keeping the temperature below 0 C. Theresulting mixture is then stirred and allowed to warm to 25 C. during 3hours. Evaporation under reduced pressure gives a residue which isdissolved in 650 ml. of anhydrous diethyl ether. The solution is cooledto 0 C., and 3 normal aqueous sodium hydroxide solution 172 ml.) isadded dropwise under nitrogen and with vigorous stirring during 15minutes, keeping the temperature of 0 to 5 C. Next, 30 percent aqueoushydrogen peroxide (94 ml.) is added dropwise with stirring during 30minutes at 0 to 5 C. Then, 500 ml. of saturated aqueous sodium chloridesolution is added, and the diethyl ether layer is separated. The aqueouslayer is washed with four 200 ml. portions of ethyl acetate, thewashings being added to the diethyl ether layer, which is then washedwith saturated aqueous sodium chloride solution, dried, and evaporatedto give 1 15 g. ofa residue. This residue is distilled under reducedpressure to give 69 g. of a mixture of the methyl esters ofendobicyclo[3.l.O]hexan-3-ol-6-carboxylic acid and endobicyclo[ 3. l.0]hexan-2-ol-6-carboxylic acid; b.p. 8695C. at 0.5 mm.

Part A-2 Endo-bicyclo[3. l .0]hexan-3-ol-6- carboxyiic I acid methylester tetrahydropyranyl ether The 2-ol and 3-ol mixture (66 g.) obtainedaccording to Part A-l in 66 ml. of dihydropyran is stirred and cooled at15-20C. during addition of 3 ml. of anhydrous diethyl ether saturatedwith hydrogen chloride. The temperature of the mixture is then kept inthe range 20 to 30 C. for one hour with cooling, and is then kept at 25for 15 hours. Evaporation gives a residue which is distilled underreduced pressure to give 66 g. of a mixture of the methylesters-tetrahydropyranyl ethers .of endobicyclo[3.l.0]hexan-3-ol-6-carboxylic acid and endobicyclo[3.l.0]hexan-2-ol-6-carboxylicacid; b.p. 96-104C. at 0.1 mm.

Part A-3 hydroxymethylbicyclo[3.1.0]hexan-3-ol-3- tetrahydropyranyiether A solution of the mixture (69 g.) of products obtained accordingto Part A-2 in 300 ml. of anhydrous diethyl ether is added dropwiseduring 45 minutes to a stirred and cooled mixture of lithium aluminumhydride (21 g.) in 1300 ml. of anhydrous diethyl ether Endo-6- undernitroge. The resulting mixture is stirred 2 hours at 25 C., and is thencooled to C. Ethyl acetate (71 ml.) is added. and the mixture is stirred15 minutes. Water (235 ml.) is then added, and the diethyl ether layeris separated. The water layer is washed twice with diethyl ether andtwice with ethyl acetate. A solution of Rochelle salts is added to theaqueous layer, which is then saturated with sodium chloride andextracted twice with ethyl acetate. All diethyl ether and ethyl acetatesolutions are combined, washed with saturated aqueous sodium chloridesolution, dried, and evaporated to give 61 g. of a mixture of the 3-tetrahydropyranyl ethers of endo-o-hydroxymethylbicicyl-[3.1.0]hexan-3oland endo-6- hydroxymethylbicyclo[3.1.0]-hexan-2-ol.

Part A-4 Endo-bicyclo[3.1.0]hexan-3-ol-6- earboxaldehyde 3-tetrahydropyranyl ether A solution of the mixture (34 g.) of productsobtained according to Part A-3 in 1000 ml. of acetone is cooled to 10C.Jones reagent (75 ml. of a solution of 21 g. of chromic anhydride, 60ml. of water, and 17 ml. of concentrated sulfuric acid), precooled to0C., is added dropwise with stirring during 10 minutes at 10 C. After 10minutes of additional stirring at 10C., isopropyl alcohol (35 ml.) isadded during minutes, and stirring is continued for minutes. Thereaction mixture is then poured into 8 of an ice and water mixture. Theresulting mixture is extracted 6 times with dichloromethane. Thecombined extracts are washed with aqueous sodium bicarbonate solution,dried, and evaporated to give 27 g. of a mixture of thetetrahydropyranyl ethers of endo-bicyclo[3.l.Olhexan3-ol-6-earboxaldehyde (XL) and endo-bicyclo[3.1.0]hexan- 2-ol -carboxaldehyde.

Part B 3-Hexynyl-1triphenylphosphonium bromide To a solution of 130 g.(0.81 moles) of l-bromo-hex- 3-yne in 250 ml. of benzene is added 236 g.(0.9 moles) of triphenylphosphine. The resulting solution is heated withstirring in a heating bath of 80 C. for 24 hours. Stirring is continuedat room temperature for 24 hours, then the reaction mixture is allowedto stand for 48 hours. An oil precipitated. The supernatant solution isdecanted, the oil stirred in 200 ml. of benzene. The oil is againallowed to separate and the supernatant solution separated. The oil isdried under vacuum at room temperature, the oil solidifies while drying.The decanted solutions are combined and heated at 80 C. bath temperaturefor 48 hours, workup as above resulted in a second batch of solidmaterial making a total yield of 210 g. of3-hexynyl-l-triphenyl-phosphonium bromide.

CHO

105 g. of the phosphonium salt of Part B is stirred in 1200 ml. of drytetrahydrofuran under a nitrogen atmosphere. The reaction flask iscooled in an ice-methanol bath. 150 ml. of a 15.1 percent hexanesolution of nbutyl lithium is added dropwise. When the addition wascomplete, stirring is continued for 20 minutes. Then a solution of 42 g.of aldehyde XL in 150 ml. tetrahydrofuran is added dropwise withstirring over a period of 15 minutes.

The ice-methanol bath is replaced by a heating bath and the reactionmixture is heated at 70 C. bath temperature for 3 hours. The reactionmixture is allowed to stand at room temperature overnight. The solventis removed under reduced pressure. The residue is treated with 500 ml.benzene and filtered; the solid is washed with 500 ml. benzene, thebenzene solutions combined and evaporated under reduced pressure. Theresulting oil is triturated with 500 ml. of Skellysolve B (technicalhexane), filtered and the resulting solution evaporated under reducedpressure to give 37 g. of a yellow oil. The oil is chromatographed using1500 g. of silica gel. The column is developed with seven 1500 ml.portions of 1:1 benzene-Skellysolve B", seven 1500 ml. portions ofbenzene, five 1,500 ml. portions of benzene containing 5 percent ethylacetate, five 1,500 ml. portions of benzene containing 10 percent ethylacetate, and three 1500 ml. portions of ethyl acetate. Fractions 12-18are combined to give a total of 12.9 g. of tetrahydropyranylether XLl asa colorless oil, fractions 19-26 are combined to give a total of 13.5 g.of the corresponding alcohol XLll as a colorless oil.

Part D Endo-6-hept-1-en-4-ynyl-bicyclo[3.1.0lhexan-3-ol (XLII) XLll 12.8g. of tetrahydropyranylether XLl is dissolved in 300 ml. of methanol,600 mg. of oxalic acid is added and the solution heated under reflux for1.5 hours. The methanol is evaporated under reduced pressure, theresulting residue dissolved in 300 ml. of methylene chloride, washedwith ml. of saturated aqueous l-laH- CO and dried over Na SO Evaporationof solvent results in 11.2 g. of crude alcohol XLII. The alcohol iscombined with alcohol XLII obtained in Part C and used for Part Ewithout further purification.

Part E Endo-6-hept-l-en-4-ynyl-bicyclo[3.1.0]hexan-3-one (XLlII) XL| llQ/i -J XLl I A solution of 23.7 g. of alcohol XLll in 720 ml. ofaceaddition is complete, stirring is continued for 10 minutes at 5C. 24ml. ofisopropanol is added and stirring continued for 10 minutes. Thegreen solution is poured into 5 liters of water and the aqueous solutionextracted with five 1 liter portions of methylene chloride. The combinedextracts are washed with 750 ml. of satu rated aqueous NaHCO two 750 ml.portions of saturated aqueous NaCl, and dried over Na SO Evaporation ofsolvent under reduced pressure yields 18.2 g. of a brown oil which ischromatographed using 800 g. of silica gel. The column is developed withfour 800 ml. portions of Skellysolve B containing 2.5 percent ethylacetate and twelve 800 ml. portions of Skellysolve B containing 5percent ethyl acetate. Fractions 9-14 are combined to yield 5.3 g. ofketone XLlll as a colorless oil.

NMR: 1 H at 5.4 5.98 (multiplet), l H at 4.7 5.26 (multiplet), 2 H at2.75 3.08; 9 H at 1.4 2.758, 3 H at 0.9 1.38 (triplet). Part F Endo-(6-heptl -en-4-ynyl )-2-( 6-carboxyhex-2-yn-a-yl)-bicyclo[3.1.0]hexan-3-one methyl ester (XLIVa) COECHS Asolution of 8.1 g. of ketone XLIll and 34.4 g. of methyl7-iodo-hept-5ynoate in 300 ml. of dry tetrahydrofuran is stirred at roomtemperature under a nitrogen atmosphere. A solution of 7.16 g. ofpotassium tbutoxide and 6.67 g. of dicyclohexyl-l8-crown-6 (Pedersen, J.Am. Chem. Soc. 89, 7017, 1967) in 450 ml. of dry tetrahydrofuran isadded dropwise over a period of 1.5 hours. Stirring is continued for 10minutes, then 75 ml. of 1N HCl is added followed by 900 ml. of saturatedaqueous NaCl solution. The reaction mixture is extracted with three 750ml. portions of ether, the extract washed with two 450 ml. portions ofpercent aqueous Na S O and 450 ml. of saturated aqueous NaCl solution,and dried over Na SO The solvent is removed under reduced pressure togive 34 g, of a brown oil which is chromatographed using 1 kg. of silicagel. The column is developed with ten 1 liter portions of Skellysolve Bcontaining 2.5 percent ethyl acetate, ten 1 liter portions ofSkellysolve B containing 5 percent ethyl acetate, and ten 1 literportions of Skellysolve B containing percent ethyl acetate. Fractions21-24 are combined to give 1.6 g. of keto-ester XLlVa as a colorlessoil.

NMR: 2 H at 4.7 5.98 (multiplet), 3 H at 3.638(singlet). Mass spectrum:peaks at 326 (M*), 311 (m-lS), 295

(M-3 1 Part G Endo-6-(l,2-dihydroxy-hept-4-ynyl)-2-(6-carboxyhex-2-yn-ct-yl)bicyclo[3 1 .O]hexan-3-one methyl ester (XLV)XLlVo:

LII

A solution of 1.47 g. of keto-ester XLlVSin 8 ml. of dry pyridine isstirred and cooled in an ice-methanol bath. 1.14 g. of osmium tetroxideis added and the reaction mixture allowed to stir in the meltingice-methanol bath overnight. A solution of 2 g. of NaHSO in 30 ml. ofwater is added and stirring continued at room temperature for 2 hours.250 ml. of ethyl acetate is added and the mixture dried over 60 g. ofNa- SO Evaporation of solvent under reduced pressure yields 1.28 g. of adark brown oil which is chromatographed using 125 g. of silica gel. Thecolumn is developed with eleven 125 ml. portions of a 1:1 mixture ofethyl acetate and Skellysolve. Fractions 41 1 are combined to yield 504mg. of glycol XLV. a mixture of the racemates of two diastereoisomers,as a colorless oil.

NMR: no vinyl protons, only protons between 0.9 and 4.36, 3 H at 3.638(singlet), 3 H at 0.95 1.38 (triplet).

The two diastereomeric racemates are separated by chromatography and theseparated racemates resolved by the method of Corey et al.. J. Am. Chem.Soc. 84. 2938 (1962) which involves reacting this keto compound withoptically active L(+)-2,3-butanedithiol in the presence of p-toluenesulfonic acid and separating the resulting diasteromcric ketals on apreparative chromatograph column and then by hydrolyzing the separateddiasterisomers. There is thus obtained the d and the forms of bothdiasteroisomers. making four enantiomorphs in all.

Part H Racemic 5,6,17,18-dchydro-PGE methyl ester (XLVLS) and itsl5-epimer (XLVLR) CO CH XLVI(S) COECHS S 0H XLVl (R) A solution of 650mg. of glycol XLV in 20 ml. of dry pyridine is stirred under a nitrogenatmosphere in an ice bath. 2 ml. of methanesulfonylchloride is added,and the mixture stirred in the ice bath for 1.5 hours, then at roomtemperature for 1 hour. The mixture is cooled in an ice bath and dilutedwith 30 ml. of ice water, after stirring for 10 minutes the mixture isextracted with three 100 ml. portions of ethyl acetate. The extract iswashed with ml. ice cold 10 percent aqueous H 50 70 ml. ice cole 10percent aqueous Na CO and two 70 ml. portions of ice cold saturatedaqueous NaCl solution. The ethyl acetate solution is dried over Na SOEvaporation of the solvent under reduced pressure yielded 870 mg. of abrown oil which is dissolved in 20 ml. of acetone, 10 ml. of water isadded and the solution allowed to stand at room temperature overnight.The acetone is removed under reduced pressure, the aqueous solutiondiluted with 25

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 1. An optically activecompound of the formula:
 2. A compound according to claim 1 wherein R1is hydrogen or alkyl of one to 4 carbon atoms, inclusive, or apharmacologically acceptable salt thereof when R1 is hydrogen.
 3. Anoptically active compound according to claim 2 wherein the side-chainhydroxy is in S configuration.
 4. A compound according to claim 3wherein R3 and R4 are hydrogen.
 5. A compound according to claim 4wherein n is one.
 6. A compound according to claim 5 wherein A istrimethylene.
 7. A compound according to claim 6 wherein R2 is ethyl. 8.5,6,17,18-dehydro-PGF3 , a compound according to claim 7 wherein R1 ishydrogen.
 9. A compound according to claim 3 wherein R3 is methyl and R4is hydrogen.
 10. A compound according to claim 9 wherein n is one.
 11. Acompound according to claim 10 wherein A is trimethylene.
 12. A compoundaccording to claim 11 wherein R2 is etHyl. 13.5,6,17,18-dehydro-15-methyl-PGF3 , a compound according to claim 12wherein R1 is hydrogen.
 14. An optically active compound of the formula:15. An optically active compound according to claim 14 wherein theside-chain hydroxy is in S configuration, and wherein R1 is hydrogen oralkyl of one to 4 carbon atoms, inclusive, or a pharmacologicallyacceptable salt thereof when R1 is hydrogen.
 16. A compound according toclaim 15 wherein R2 is ethyl, and R3 and R4 are both hydrogen.
 17. Acompound according to claim 16 wherein b is one.
 18. A compoundaccording to claim 17 wherein Z is ethylene substituted with 2 fluoro onthe carbon atom alpha to the carboxylate function.
 19. A compoundaccording to claim 17 wherein Z is ethylene substituted with one methylon the carbon atom beta to the carboxylate function.
 20. A compoundaccording to claim 15 wherein R2 is ethyl, R3 is alkyl of one to 4carbon atoms, inclusive, and R4 is hydrogen.
 21. A compound according toclaim 20 wherein b is one.
 22. A compound according to claim 21 whereinZ is ethylene substituted with 2 fluoro on the carbon atom alpha to thecarboxylate function.